Design, synthesis and inhibitory activity against human dihydroorotate dehydrogenase (hDHODH) of 1,3-benzoazole derivatives bearing amide units

Jiling Li; Dang Wu; Xiaoyong Xu; Jin Huang; Xusheng Shao; Zhong Li

doi:10.1016/j.bmcl.2016.05.016

Design, synthesis and inhibitory activity against human dihydroorotate dehydrogenase (hDHODH) of 1,3-benzoazole derivatives bearing amide units

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3064-3066. doi: 10.1016/j.bmcl.2016.05.016. Epub 2016 May 7.

Authors

Jiling Li¹, Dang Wu¹, Xiaoyong Xu¹, Jin Huang¹, Xusheng Shao², Zhong Li³

Affiliations

¹ Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: shaoxusheng@ecust.edu.cn.
³ Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: lizhong@ecust.edu.cn.

PMID: 27220723
DOI: 10.1016/j.bmcl.2016.05.016

Abstract

A series of 1,3-benzoazole derivatives possessing amide moieties were designed, synthesized and evaluated as inhibitors against human dihydroorotate dehydrogenase (hDHODH). Compounds A11, A14 and A26 exhibited good to excellent activities against hDHODH at the concentration of 10μM. In particular, compound A14 displayed an IC50 value of 0.178μM with 2-fold preference over A771726. The result implied that a proper degree of steric size and electron density of the C-6 amide moiety was necessary to retain the inhibitory activity of the synthesized compounds.

Keywords: 1,3-Benzoazole; Activity; Amide; Scaffold hopping; hDHODH.

MeSH terms

Amides / chemical synthesis
Amides / chemistry*
Aniline Compounds / chemistry
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Crotonates
Dihydroorotate Dehydrogenase
Drug Design
Humans
Hydroxybutyrates / chemistry
Nitriles
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / chemistry
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Structure-Activity Relationship
Toluidines

Substances

2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-N-(2-fluorophenyl)-1H-benzo(d)imidazole-7-carboxamide
Amides
Aniline Compounds
Benzimidazoles
Crotonates
Dihydroorotate Dehydrogenase
Hydroxybutyrates
Nitriles
Pyrazoles
Toluidines
teriflunomide
Oxidoreductases Acting on CH-CH Group Donors